Tissue-engineering methods for the repair of damaged tissue include (i) forming a tissue from expanded and cultured cells, and transplanting said tissue, (ii) loading expanded and cultured cells at a scaffold and transplanting said scaffold, or (iii) transplanting a scaffold only without cells.
In the case of cartilage regeneration, expanded and cultured cells can be cultured in a chondrogenic medium to form cartilage which is transplanted into a damaged region of cartilage to induce regeneration of cartilage. This method has the advantage of being able to get a definitive therapeutic effect, compared with a method of injecting cells. However, in case the transplanted cartilage tissues do not integrate into the existing tissues, a full therapeutic effect cannot be expected.
This integration (connectivity) may be achieved by carrying out a suture, but in this case the subject tissues must have a structure that can be connected by a suture. It is impossible to apply a suture to a tissue having a structure that cannot be sutured. For example, a tissue that makes up cartilage or bone has limitations for having a suture applied thereon. In particular, when a connection between bone and cartilage is necessary as is in, for instance, the articular cartilage transplantation, it is not easy to carry out such a suture method and there is the shortcoming that a suture area has the potential to cause inflammation. Furthermore, in the case of widely occurring cartilage damage such as degenerative arthritis, it is not easy to find a way to achieve a connection of tissues over a large area.
In order to resolve these problems, a bio-adhesive agent in the form of a paste has been developed which exhibits an adhesive effect between cartilage and cartilage. However, this agent has a major disadvantage due to the fact that the applied adhesive materials formed insulation between the two attached cartilage tissues making it impossible to communicate or exchange the nutrient and/or growth factors and thus two different disconnected cartilage layers are formed bordering the attached surface. Moreover, the previously developed bio-adhesive agents are not effective in achieving a connection (adhesion) between bone and cartilage in the full-thickness wound.
Therefore, there is a need to develop a new bio-adhesive agent that is suitable for the desired tissue regeneration.
Hydroxyapatite is an inorganic substance that constitutes calcified tissues in vivo such as teeth and bone. Hydroxyapatite has the highest crystallinity among calcium phosphate compounds, so its speed of decomposition is accordingly slow, but it has high bio-compatibility as it is a substance comprising natural tissues in vivo. Hydroxyapatite is known to represent the most high bone regeneration effect among various kinds of bone substitutes.
In the previous study, the present inventors devised a method for coating a desired functional group on the surface of hydroxyapatite. Specifically, PCT Publication No. WO 2009/073068, which is an earlier application by the present inventors, disclosed an artificial bone sponge prepared by a process that comprises: modifying the surface of hydroxyapatite using an organic synthesis method so that a functional group such as aldehyde is revealed on the surface of hydroxyapatite; mixing the obtained surface-modified hydroxyapatite with an aqueous solution of chitosan for gellation; and lyophilizing the same. However, WO 2009/073068 teaches only the combination with a second ingredient such as chitosan and does not teach a use of the surface-modified hydroxyapatite alone.
The present inventors have performed continuous study on a use of the surface-modified hydroxyapatite alone without addition of a second ingredient such as chitosan. As a result, they discovered that the surface-modified hydroxyapatite exhibits a satisfactory adhesive strength between bone and cartilage, confirming its potential as a new bio-adhesive agent, and completed the present invention.